Investigators at the University of California, San Diego propose their continued inclusion as a Clinical Center within the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN). NASH is the most prevalent liver disease in children and one of the most common causes of chronic liver disease in adults. NASH is associated with cardiovascular disease risk factors such as type 2 diabetes, hypertension, dyslipidemia and obesity. The Network's broad, long-term objectives are to advance understanding of the pathogenesis, natural history, genetics, histopathology and treatment for NASH. The NASH CRN currently is conducting 2 multi-center, double-blind, randomized, placebo-controlled clinical trials which require completion in the renewal period, one In children 8-17 years inclusive and the other in adults 18 years and over. The pediatric study called TONIC, has 173 subjects enrolled for a 2-year treatment, assessing safety and efficacy of metformin or Vitamin E versus placebo. The adult study called PIVENS, has 247 subjects enrolled for 2-years of treatment to assess pioglitazone or Vitamin E versus placebo. Additionally, there is a genetics study called GOALS, which requires many more children and their parents to enroll in order to identify candidate genes associated with NASH, and an ongoing Database study with 1262 current subjects intended to assess the natural history of NASH. The Database also will be invaluable for evaluating life-style factors in NASH and evaluating noninvasive biomarkers and imaging for diagnosis and progression. In this renewal we aim to expand the database with under-represented and important biopsy-proven sub-populations such as children (particularly girls), Hispanics, blacks and those with cirrhosis to better understand the role of age, gender, ethnicity, race, genetics and lifestyle in the development of NASH and Its co-morbidities. We aim to Identify appropriately matched control populations without NAFLD to permit comparisons to those with NAFLD. We propose the conduct of another randomized placebo-controlled clinical trial to assess other treatment options for children with NASH, and we will complete, analyze and report on the treatment studies from the last grant period now coming to fruition.